SPECT myocardial perfusion imaging provides critical information concerning the severity and functional significance of coronary artery disease (CAD). It has now been demonstrated that correction for attenuation, scatter, and spatial resolution significantly improves the diagnostic accuracy of perfusion SPECT imaging. The goal of the research of this proposal is to further improve the detection accuracy of SPECT for CAD through perfecting the transmission imaging strategy used in the estimation of patient-specific attenuation maps, and developing compensation strategies for respiratory motion of the heart and surrounding structures, the presence of significant extra-cardiac activity close to the heart, and partial volume effect caused differences in apparent maximal wall counts. The investigations will be carried out by a mixture of simulation, phantom, and clinical studies. The first specific aim is to develop the next-generation of transmission imaging which consists of cone-beam transmission imaging of point-sources whose highenergy photons penetrate through parallel-hole collimators as an accurate, practical, and robust alternative to present commercial transmission-imaging geometries for the estimation of attenuation maps for use specifically with cardiac imaging. Tasks to be accomplished include the optimization of point source shielding, number, geometry of placement, extent of axial and angular coverage, and modeling of the physics of transmission imaging in the reconstruction algorithm. The second specific aim is to develop a compensation strategy which will significantly reduce limitations to cardiac-wall visibility and apparent nonuniformity of perfusion caused by respiratory motion. Correction of respiratory motion both in emission and transmission imaging will be explored. The third specific aim is to investigate methods to diminish the interference of extra-cardiac activity with myocardial wall visibility and appearance of perfusion defects. The fourth specific aim is to formulate a correction method for the impact of the partial volume effect on the apparent uniformity of myocardial counts. The proposed method will assume that high spatial-resolution cardiac anatomy is available from a second imaging modality. The fifth specific aim is to investigate with clinical ROC studies the impact on the accuracy of CAD detection of the above compensation strategies. The use of normal clinical acquisitions to which defects are inserted mathematically (hybrid images) will be investigated as an alternative to the collection of clinical studies with "known" truth as to the presence of CAD for ROC comparisons of detection accuracy.